Peptide antigens recognized by human melanoma-reactive T cells can be incorporated in vaccines to induce immune responses against melanoma. To date, most vaccine regimens have been limited to the use of single antigens, or a few antigens targeting the activation of CD8+ T cells. While CD8+ T-cell responses following vaccination have been noted, they are often low in magnitude, and objective clinical responses are limited. To improve vaccine strategies, it may help to increase the number of antigens targeted, to increase the magnitude of responses, to target both CD4 and CD8* T cells, and to increase persistence of the immune response through induction of memory. CD4 responses appear to be critical for immunologic memory, and for dendritic cell activation. With the recent identification of melanoma-associated MHC class ll-restricted peptides, it is feasible to assess their immunogenicity, and to determine whether they have an impact, on the magnitude and persistence of CD8+ T-cell responses. The immunologic effects of vaccination with a multipeptide vaccine targeting CD4+ and CD8+ T cells will be evaluated in the proposed clinical trial. Furthermore, we will address whether pre-treatment with a single dose of cyclophosphamide (CY) augments immunogenicity of a multipeptide vaccine. When administered at a dose inferior to that used for tumor lysis, CY has been shown to augment immune responses against KLH and cellular immunogens in humans. The proposed study is unique in that we will be evaluating the effects of this dose of drug in the setting where specific immune responses against target antigens can be quantified and measured. The peptide antigens used in this trial include (i) a cocktail of 12 melanoma peptides restricted by Class I MHC molecules HLA-A1, A2, or A3 (12MP), (ii) a cocktail of 6 melanoma helper peptides restricted by HLA-DR molecules (6MHP), and (iii) a modified tetanus peptide restricted by HLA-DR molecules (tet-p). Patients with resected IIB-IV melanoma will be randomized to one of four vaccine strategies: (a) 12MP + tet-p, (b) CY + 12MP + tet-p, (c) 12MP + 6MHP, and (d) CY + 12MP + 6MHP. The following specific aims will be addressed: 1) Determine whether addition of melanoma-associated helper peptides to a vaccine containing multiple Class I MHCrestricted peptides augments T-cell responses to the Class I MHC-restricted peptides, in patients treated in the adjuvant setting, 2) Determine the CD4+ T-cell response to helper peptides included in this vaccine, 3) Determine whether pre-treatment with a single dose of cyclophosphamide augments immunogenicity of a multipeptide vaccine, and 4) Obtain preliminary estimates of the impact of vaccination and vaccine responses on clinical outcome.